N-Phenyl-N′-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents. Part 3: Role of carbonyl groups in the covalent binding to the colchicine-binding site

Emmanuel Moreau (1) , Sébastien Fortin (2) , Jacques Lacroix (3) , Alexandre Patenaude , Jean L C Rousseau , René C-Gaudreault , Jean L.C. Rousseau

1 IMoST - Imagerie Moléculaire et Stratégies Théranostiques
2 ISIT - Image Science for Interventional Techniques
3 Unité des Biotechnologies et de Bioingénierie

In the course of the development of N-phenyl-N'-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents, we investigated the effect of carbonylated substituting chains of the aromatic ring of CEU on their covalent binding to the colchicine-binding site (C-BS). In this study, we found that CEU, 5e, 5f, 8e, and 8f substituted by either a methyl ester or a methyl ketyl group at the omega-position exhibited a significant antiproliferative activity on HT-29, M21, and MCF-7 tumor cells. SDS-PAGE assays and cell cycle analysis confirmed that 5e, 5f, 8e, and 8f covalently bind to the C-BS and arrest the cell division in G(2)/M phase. Surprisingly, the presence of omega-carboxyl, omega-ethyl esters or omega-amides decreased significantly both the antiproliferative activity and the specificity toward beta-tubulin.

Domaines: Chimie organique; Radiochimie; Chimie thérapeutique; Chimie de coordination

Emmanuel Moreau, Sébastien Fortin, Jacques Lacroix, Alexandre Patenaude, Jean L C Rousseau, et al.. N-Phenyl-N′-(2-chloroethyl)ureas (CEUs) as potential antineoplastic agents. Part 3: Role of carbonyl groups in the covalent binding to the colchicine-binding site. Bioorganic and Medicinal Chemistry, 2008, 16 (3), pp.1206 - 1217. ⟨10.1016/j.bmc.2007.10.078⟩. ⟨hal-01677581⟩